Summary/Abstract Background: Traumatic brain injury (TBI) is considered to be the signature injury of our current wars with over 20% of our military service members experiencing at least one TBI exposure during deployment. Persons with TBI often suffer significant functional and neurological morbidity requiring informal caregivers to assume responsibility for the individual's familial, social, and financial obligations. Although research investigating the health of TBI informal caregivers is sparse, literature consistently indicates that, in general, caregivers are at risk for developing depression, anxiety, altered immune function, health problems, and poor quality of life. Recent evidence demonstrates that chronic stress leads to loss of the ability of cortisol to attenuate stress-induced release of inflammatory cytokines. This may increase the risk for developing inflammatory -related disease. The purpose of this study is to collect pilot data to enable future research focusing on the reduction of chronic stress in informal caregivers of service members and veterans with TBI. The primary aim is to (1) Explore the relationships among stress (perceived stress, chronic stress, and caregiver burden), physiological measures of stress (salivary cortisol and inflammatory cytokines), health-promoting behavior, health care utilization, physical and psychological health, and perceived quality of life of informal caregivers of TBI individuals. Secondary aims are to assess recruitment strategies and feasibility of data collection methods and to calculate effect sizes of measures for future studies. Project Methods: A prospective, cross-sectional, correlational methodology will be used. A convenience sample of 44 informal caregivers caring for a military service member or veteran who has experienced a moderate or severe TBI within the past 1 to 6 years will be enrolled. Participants will be limited to females in order to control for gender influences on physiologic measures. Other inclusion criteria are age 18 or older and ability to write, speak, and understand English. Standardized measures of perceived stress, chronic stress, caregiver burden, health promoting behavior, health care utilization, somatic symptoms, perceived health, mood, depression, and perceived quality of life will be collected. Social support and socioeconomic status will be examined as potential confounders. Participants will collect saliva samples five times a day (upon awakening, 30 minutes after awakening, 12 noon, 5 PM, and bedtime) for two consecutive days. All data will be returned to the investigator via Fedex in postage -paid biohazardous compliant packaging. Saliva samples will be centrifuged and frozen for later batch analyses using enzyme- linked immunoassays. Descriptive statistics and correlations will be used to identify trends. This study will provide new findings to help fill gaps in knowledge of psychological stress and physiological sequelae of caregiving for individuals with TBI. The findings will be used to evaluate the feasibility of the proposed measures and provide the foundation for a larger, longitudinal, interventional study aimed at reducing chronic stress in informal caregivers of TBI military service members and veterans. Importantly, this pilot study will evaluate the feasibility of including biomarkers to measure the effectiveness of a stress-reduction intervention in a future study. Optimizing health and quality of life of informal caregivers is integral to successfully caring for our military service members and veterans who experienced a TBI.